bims-oxygme 2025-10-12 papers

Issue of 2025–10–12
five papers selected by
Onurkan Karabulut, Berkeley City College

Cell Commun Signal. 2025 Oct 08. 23(1): 420

BMAL1 modulation alleviates inflammatory responses in monocytes by targeting the Fis1-mediated mitochondrial unfolded protein response in high-altitude hypoxia.

Yi-Ling Ge, Jin Xu, Yue Cai, Bin Zhang, Si-Yuan He, Pei-Jie Li, Ying-Rui Bu, Lin Zhang, Zhi-Bin Yu, Heng Ma, Yong Liu, Xiong-Wen Chen, Man-Jiang Xie.

BACKGROUND: Hypoxia-induced inflammation has been implicated in the progression of high-altitude illnesses. Mitochondria are key organelles for oxygen metabolism and inflammation that are controlled by circadian clocks. However, little is known regarding how circadian clocks sense hypoxic signals and trigger downstream mitochondrial responses.
METHODS: Human participants and mice were exposed to a real or simulated high-altitude setting of 5500 m. Multichannel fluorescence intravital microscopy was used for in vivo molecular imaging of inflammation. Bioinformatics analysis, myeloid-specific knockout mice, and RAW 264.7 cells were used to investigate the underlying inflammatory mechanisms.
RESULTS: We found that high-altitude hypoxia induced dynamic inflammatory activity in monocytes, characterized by significantly increased levels of cytokines (interleukin-6 [IL-6], IL-1β and monocyte chemoattractant protein-1) after acute (3-day) exposure, which returned to control levels after a prolonged (30-day) exposure. Bioinformatics analysis revealed that the core circadian transcription factor brain and muscle Arnt-like 1 (BMAL1) correlated positively with hypoxia-induced inflammation in monocytes. Mechanistically, BMAL1 induced NOD-like receptor protein 3 inflammasome activation in monocytes by targeting the Fis1-mediated mitochondrial unfolded protein response. Basic helix-loop-helix family member E40, a hypoxic stress-responsive transcription factor, directly promoted Bmal1 transcription and triggered inflammation in monocytes. In contrast, myeloid-specific deletion of BMAL1 alleviated the inflammatory activity of monocytes and circulating inflammation, both in vitro and in vivo, under high-altitude hypoxia.
CONCLUSIONS: Our findings indicate that transcriptional activation of Bmal1 in monocytes can potentially serve as a novel biomarker of hypoxia-induced inflammation. Our findings also suggest a novel approach for modulating the intrinsic clock, which might render organisms less vulnerable to high-altitude hypoxia.

Keywords: BMAL1; High-altitude hypoxia; Inflammatory response; Mitochondrial unfolded protein response

DOI: https://doi.org/10.1186/s12964-025-02420-8

Br J Nutr. 2025 Oct 10. 1-41

2,3-diphosphoglycerate: The Forgotten Metabolic Regulator of Oxygen Affinity.

Layal S Jaafar, Christina Mary R Kourie, Carla A El-Mallah, Omar Obeid.

2,3-Diphosphoglycerate (2,3-DPG), a metabolic intermediate in the Rapoport-Luebering pathway, is primarily present in red blood cells and regulates the affinity of hemoglobin (Hb) to oxygen. As the 2,3-DPG level in the erythrocyte increases, the oxygen dissociation curve shifts to the right, thus decreasing the oxygen affinity of Hb. This alteration in oxygen affinity is crucial for maintaining adequate oxygen supply to peripheral tissues, especially under hypoxic conditions such as high-altitude adaptation and anemia. Despite its crucial role in regulating oxygen affinity and its potential function as a modulator in various physiological and pathological adaptations, much of the research on 2,3-DPG is outdated and has largely been overlooked in recent years. The aim of this review is to compile the existing evidence on 2,3-DPG and highlight the gaps in our current understanding.The erythrocyte concentration of 2,3-DPG can be determined using chromatography or enzymatic methods. However, assessing 2,3-DPG poses a challenge due to its instability, which can rapidly degrade in the absence of proper storage conditions. Several factors can impact the erythrocyte concentration of 2,3-DPG, including diet, physiological conditions, and pathological conditions. Dietary intake, particularly phosphorus, can acutely influence 2,3-DPG levels in red blood cells. However, no information is available on the postprandial status of 2,3-DPG following the ingestion of meals with varied nutrient composition. Additionally, physiological factors such as age, pregnancy, and physical activity can affect 2,3-DPG levels, but its role during infancy and childhood is still not well understood. Although the levels of 2,3-DPG in various pathological conditions have been widely discussed, the underlying molecular mechanisms regulating these changes are still not well understood and require further investigations.

Keywords: 2,3-diphosphoglycerate; Erythrocyte; Glycolysis; hemoglobin; oxygen affinity

DOI: https://doi.org/10.1017/S0007114525105345

Front Physiol. 2025 ;16 1641343

Human red blood cell ATP content and export under hypoxic and/or isocapnic storage conditions.

Youwei Chen, Cole Darrow, Aidan Murray, Thomas Wise, Zhong Lucas Li, Nisha Srivastava, Hongmei Zhu, Ian J Welsby, Tatsuro Yoshida, Tim J McMahon.

Introduction: In some diseases driving or associated with anemia, red blood cell (RBC) transfusion conveys limited benefit, and only when the anemia is severe. The banking of RBCs alters key molecules and functions. Among these changes during blood banking, depletion of the allosteric effector 2,3-BPG (biphosphoglycerate) takes place in the first two to 3 weeks, while ATP depletion only becomes prominent in the fifth or sixth (i.e., final) weeks of storage. One approach to testing the significance of these changes is to test the effects in vitro and in vivo of stabilizing key molecules. We hypothesized that hypoxic RBC storage, which can stabilize RBC BPG and ATP generation, could in turn stabilize the ability of RBCs to export vasoactive ATP, an activity that modulates RBC functions including O2 delivery.
Methods: We performed a parallel study of conventional RBCs, hypoxically stored (Hemanext) RBCs ("HN-Std RBCs"), and CO2-preserved, hypoxically stored RBCs ("HN + CO2 RBCs").
Results and discussion: Standard hypoxic RBC storage boosted RBC ATP content, peaking in mid-storage. The time course of P50 (a measure of RBC Hb O2 affinity) changes in hypoxically stored RBCs corresponded to that of superior preservation of BPG, peaking in the first one to 2 weeks of storage. CO2-preserved hypoxic RBCs preserved ATP within the first week of storage, but with little effect on BPG or P50 at any time point. ATP export from RBCs assessed in normoxia or hypoxia declined over storage time, and generally did not differ significantly as a function of hypoxic storage ± CO2 preservation. An exception was the 1-week timepoint, when ATP export was significantly greater by HN + CO2 stored RBCs than by HN-Std stored RBCs. Taken together, these findings demonstrate time-dependent, differential modulation of RBC ATP and BPG by hypoxic RBC storage with or without CO2 preservation. Overall, hypoxic RBC storage ± CO2 preservation neither promotes nor restricts RBC ATP export to a large extent as compared to conventional RBC storage. Given that transfusion of hypoxically stored RBCs can be advantageous, future studies can test whether the differential and time-dependent effects on ATP, BPG and P50 can be leveraged for context-specific or personalized decision-making around RBC transfusion for anemia.

Keywords: biphosphoglycerate (BPG); blood flow; erythrocyte; oxygen binding; transfusion

DOI: https://doi.org/10.3389/fphys.2025.1641343

Burns. 2025 Sep 08. pii: S0305-4179(25)00324-9. [Epub ahead of print]51(9): 107695

Insights into hypoxia-induced impairment of autophagy in cardiomyocytes via the p38/MAPK/MAP4 pathway.

Khadijeh Saravani, Seyed Mehdi Pourafzali, Batool Heydarisadegh, Ali Alimohammadi.

Keywords: Burn; Hypoxia; Signaling pathway

DOI: https://doi.org/10.1016/j.burns.2025.107695

Arch Biochem Biophys. 2025 Oct 07. pii: S0003-9861(25)00351-0. [Epub ahead of print] 110637

Novel epigenetic biomarkers following ferroptosis and pyroptosis in a hypobaric hypoxia-induced renal injury model.

Hongxuan Liu, Huishu Lin, Yuhong He, Shuhao Shi, Jiayan Ni, Lei Zhao, Yuxuan Ma, Weixia Li, Yuanyuan Yu, Chen Li, Qisijing Liu, Shike Hou, Xiaoxue Li, Liqiong Guo.

BACKGROUND: Rapid hypobaric hypoxia exposure damages oxygen-sensitive organs like the kidneys. Ferroptosis and pyroptosis, oxygen-dependent cell death mechanisms, remain understudied in this context, as does the role of mitochondrial DNA (mtDNA) methylation.
METHODS: We established a rat model of hypobaric hypoxia (6000m/7000m, 6h/72h). Kidney ferroptosis (Prussian blue staining, LPO/MDA/GSH assays, ACSL4/GPX4 expression) and pyroptosis (Caspase1/GSDMD activation) were analyzed. mt-cox1/2/3 methylation was assessed in renal mitochondrial DNA, cytoplasmic DNA, and serum cell-free DNA (cf mtDNA) via pyrosequencing. PCA identified biomarkers.
RESULTS: Hypobaric hypoxia induced renal iron accumulation, lipid peroxidation, and tubular injury. Ferroptosis was mediated by ACSL4 upregulation and GPX4 suppression, while pyroptosis activated Caspase1/GSDMD. Mitochondrial damage and mtDNA leakage were observed via TEM. mt-cox3 pos2 hypermethylation in serum cell-free mtDNA distinctly distinguished hypoxia-exposed rats via PCA.
CONCLUSION: Ferroptosis and pyroptosis synergize to drive hypobaric hypoxia-induced renal injury. mt-cox3 pos2 methylation in cell-free mtDNA emerges as a novel biomarker for renal pathogenesis.

Keywords: Ferroptosis; Hypobaric hypoxia exposure; Kidney injury; Pyroptosis; mtDNA methylation

DOI: https://doi.org/10.1016/j.abb.2025.110637